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Does mechanism matter? Unrelated neurotoxicants converge on cell cycle and apoptosis during neurodifferentiation.

Publication ,  Journal Article
Slotkin, TA; Seidler, FJ
Published in: Neurotoxicol Teratol
July 2012

Mechanistically unrelated developmental neurotoxicants often produce neural cell loss culminating in similar functional and behavioral outcomes. We compared an organophosphate pesticide (diazinon), an organochlorine pesticide (dieldrin) and a metal (Ni(2+)) for effects on the genes regulating cell cycle and apoptosis in differentiating PC12 cells, an in vitro model of neuronal development. Each agent was introduced at 30μM for 24 or 72h, treatments devoid of cytotoxicity. Using microarrays, we examined the mRNAs encoding nearly 400 genes involved in each of the biological processes. All three agents targeted both the cell cycle and apoptosis pathways, evidenced by significant transcriptional changes in 40-45% of the cell cycle-related genes and 30-40% of the apoptosis-related genes. There was also a high degree of overlap as to which specific genes were affected by the diverse agents, with 80 cell cycle genes and 56 apoptosis genes common to all three. Concordance analysis, which assesses stringent matching of the direction, magnitude and timing of the transcriptional changes, showed highly significant correlations for pairwise comparisons of all the agents, for both cell cycle and apoptosis. Our results show that otherwise disparate developmental neurotoxicants converge on common cellular pathways governing the acquisition and programmed death of neural cells, providing a specific link to cell deficits. Our studies suggest that identifying the initial mechanism of action of a developmental neurotoxicant may be strategically less important than focusing on the pathways that converge on common final outcomes such as cell loss.

Duke Scholars

Published In

Neurotoxicol Teratol

DOI

EISSN

1872-9738

Publication Date

July 2012

Volume

34

Issue

4

Start / End Page

395 / 402

Location

United States

Related Subject Headings

  • Toxicology
  • Rats
  • PC12 Cells
  • Nickel
  • Neurons
  • Neurogenesis
  • Insecticides
  • Dieldrin
  • Diazinon
  • Cell Differentiation
 

Citation

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ICMJE
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Slotkin, T. A., & Seidler, F. J. (2012). Does mechanism matter? Unrelated neurotoxicants converge on cell cycle and apoptosis during neurodifferentiation. Neurotoxicol Teratol, 34(4), 395–402. https://doi.org/10.1016/j.ntt.2012.04.008
Slotkin, Theodore A., and Frederic J. Seidler. “Does mechanism matter? Unrelated neurotoxicants converge on cell cycle and apoptosis during neurodifferentiation.Neurotoxicol Teratol 34, no. 4 (July 2012): 395–402. https://doi.org/10.1016/j.ntt.2012.04.008.
Slotkin, Theodore A., and Frederic J. Seidler. “Does mechanism matter? Unrelated neurotoxicants converge on cell cycle and apoptosis during neurodifferentiation.Neurotoxicol Teratol, vol. 34, no. 4, July 2012, pp. 395–402. Pubmed, doi:10.1016/j.ntt.2012.04.008.
Journal cover image

Published In

Neurotoxicol Teratol

DOI

EISSN

1872-9738

Publication Date

July 2012

Volume

34

Issue

4

Start / End Page

395 / 402

Location

United States

Related Subject Headings

  • Toxicology
  • Rats
  • PC12 Cells
  • Nickel
  • Neurons
  • Neurogenesis
  • Insecticides
  • Dieldrin
  • Diazinon
  • Cell Differentiation